Read this and we get the sense that intervention is becoming
plausible for Alzheimer's and Parkinson's. We obviously have a
long ways to go unless we get simply luck, yet the shape of the
problem is be coming really clear.
We have several core problems with human biology. Arthritis and
brain disease have been the great debilitators of the aging. Cancer
has been a general early killer and can be thought of as largely
separate. Yet the three provide a deadly obstacle course for natural
aging. Eliminate all three and stabilize circulatory problems and we
have the royal road to a full lifespan of one hundred years before
interventions that rebuild our cellular environment and gain
additional centuries.
Realistically we do have to discover ways to eliminate those
particular threats. Life extension in the case of severe damage to
organs is hardly a viable option and even unwelcome to the patient.
Scientists identify
molecular trigger for Alzheimer’s disease
Researchers have
pinpointed a catalytic trigger for the onset of Alzheimer’s
disease – when the fundamental structure of a protein molecule
changes to cause a chain reaction that leads to the death of neurons
in the brain.
For the first time,
scientists at Cambridge’s Department of Chemistry have been able to
map in detail the pathway that generates “aberrant” forms of
proteins which are at the root of neurodegenerative conditions such
as Alzheimer’s.
They believe the
breakthrough is a vital step closer to increased capabilities for
earlier diagnosis of neurological disorders such as Alzheimer’s and
Parkinson’s, and opens up possibilities for a new generation of
targeted drugs, as scientists say they have uncovered the earliest
stages of the development of Alzheimer’s that drugs could possibly
target.
The study, published
today in the journal PNAS, is a milestone in the long-term research
established in Cambridge by Professor Christopher Dobson and his
colleagues, following the realisation by Dobson of the underlying
nature of protein ‘misfolding’ and its connection with disease
over 15 years ago.
The research is likely
to have a central role to play in diagnostic and drug development for
dementia-related diseases, which are increasingly prevalent and
damaging as populations live longer.
“There are no
disease modifying therapies for Alzheimer’s and dementia at the
moment, only limited treatment for symptoms. We have to solve what
happens at the molecular level before we can progress and have real
impact,” said Dr Tuomas Knowles, lead author of the study and
long-time collaborator of Professor Dobson.
“We’ve now
established the pathway that shows how the toxic species that cause
cell death, the oligomers, are formed. This is the key pathway to
detect, target and intervene – the molecular catalyst that
underlies the pathology.”
In 2010, the
Alzheimer’s Research Trust showed that dementia costs the UK
economy over £23 billion, more than cancer and heart disease
combined. Just last week, PM David Cameron urged scientists and
clinicians to work together to “improve treatments and find
scientific breakthroughs” to address “one of the biggest social
and healthcare challenges we face.”
The neurodegenerative
process giving rise to diseases such as Alzheimer’s is triggered
when the normal structures of protein molecules within cells become
corrupted.
Protein molecules
are made in cellular ‘assembly lines’ that join together chemical
building blocks called amino acids in an order encoded in our DNA.
New proteins emerge as long, thin chains that normally need to be
folded into compact and intricate structures to carry out their
biological function.
Under some conditions,
however, proteins can ‘misfold’ and snag surrounding normal
proteins, which then tangle and stick together in clumps which build
to masses, frequently millions, of malfunctioning molecules that
shape themselves into unwieldy protein tendrils.
The abnormal tendril
structures, called ‘amyloid fibrils’, grow outwards around the
location where the focal point, or 'nucleation' of these abnormal
“species” occurs.
Amyloid fibrils can
form the foundations of huge protein deposits – or plaques –
long-seen in the brains of Alzheimer’s sufferers, and once believed
to be the cause of the disease, before the discovery of ‘toxic
oligomers’ by Dobson and others a decade or so ago.
A plaque’s size and
density renders it insoluble, and consequently unable to move.
Whereas the oligomers, which give rise to Alzheimer's disease, are
small enough to spread easily around the brain - killing neurons and
interacting harmfully with other molecules - but how they were
formed was until now a mystery.
The new work, in large
part carried out by researcher Samuel Cohen, shows that once a
small but critical level of malfunctioning protein ‘clumps’ have
formed, a runaway chain reaction is triggered that multiplies
exponentially the number of these protein composites, activating
new focal points through ‘nucleation’.
It is this secondary
nucleation process that forges juvenile tendrils, initially
consisting of clusters that contain just a few protein molecules.
Small and highly diffusible, these are the ‘toxic oligomers’ that
careen dangerously around the brain cells, killing neurons and
ultimately causing loss of memory and other symptoms of dementia.
The researchers
brought together kinetic experiments with a theoretical framework
based on master equations, tools commonly used in other areas of
chemistry and physics but had not been exploited to their full
potential in the study of protein malfunction before.
The latest research
follows hard on the heels of another ground breaking study, published
in April of this year again in PNAS, in which the Cambridge group, in
Collaboration with Colleagues in London and at MIT, worked out the
first atomic structure of one of the damaging amyloid fibril protein
tendrils. They say the years spent developing research techniques are
really paying off now, and they are starting to solve “some of the
key mysteries” of these neurodegenerative diseases.
“We are essentially
using a physical and chemical methods to address a biomolecular
problem, mapping out the networks of processes and dominant
mechanisms to ‘recreate the crime scene’ at the molecular root of
Alzheimer’s disease,” explained Knowles.
“Increasingly, using
quantitative experimental tools and rigorous theoretical analysis to
understand complex biological processes are leading to exciting and
game-changing results. With a disease like Alzheimer’s, you have to
intervene in a highly specific manner to prevent the formation of the
toxic agents. Now we’ve found how the oligomers are created, we
know what process we need to turn off.”
Full bibliographic
information"Proliferation of amyloid-β42 aggregates occurs
through a secondary nucleation mechanism"
Samuel I. A. Cohena, Sara Linseb,1, Leila M. Luheshia, Erik Hellstrandb, Duncan A. Whitea, Luke Rajaha, Daniel E. Otzenc, Michele Vendruscoloa, Christopher M. Dobsona,1, and Tuomas P. J. Knowlesa,1
aDepartment of
Chemistry, University of Cambridge, Cambridge CB2 1EW, United
Kingdom; bDepartment of Biochemistry and Structural Biology, Lund
University, SE221 00 Lund, Sweden; and cDepartment of Molecular
Biology, Interdisciplinary Nanoscience Center, Aarhus University,
8000 Aarhus C, Denmark
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